Bone marrow (BM) suppression is the primary cause of death after accidental or intentional exposure to a moderate or high dose of radiation and a common side effect of cancer therapy. The mechanisms whereby IR induces BM suppression have been largely attributed to the induction of apoptosis in hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs). We have provided the foremost direct evidence showing that HSCs and HPCs die by apoptosis, not necrosis, after exposure to a moderate dose of IR. Treatment of HSCs and HPCs in vitro with a broad-spectrum caspase inhibitor, MX1013 or z-VAD, inhibited IR-induced apoptosis (without conversion to necrotic cell death) and preserved their function. Furthermore, mice treated with MX1013 or z-VAD exhibited a significant reduction in IR-induced mortality, demonstrating that the preserved HSCs had the ability to reconstitute damaged BM in vivo. In contrast, various tumor cells die not by apoptosis but by reproductive cell death in response to IR and inhibition of caspase activity with a caspase inhibitor fails to protect these cells from IR-induced clonogenic cell death. Based on these novel findings, we hypothesize that activation of caspases mediates IR-induced BM suppression by the induction of HSC and HPC apoptosis. Furthermore, caspase inhibitors are novel radioprotectants that have the potential to be developed as new mechanism-based therapeutic agents to selectively protect BM but not tumor cells from IR-induced damage. To test our hypothesis, we will determine: (1) the sequence of IR- induced caspase activation and the role of individual caspases in IR-induced apoptosis in HSCs and HPCs in vitro;(2) the radioprotective effects of MX1013 (a lead drug candidate of antiapoptotic caspase inhibitors developed by Maxim) and/or G-CSF on total body irradiation (TBI)-induced BM suppression;and (3) the effects of MX1013 on IR-induced tumor cell killing and mutagenesis and genetic instability in normal cells in a mouse model. We expect that the proposed experiments will provide new insights into the role of caspases in IR-induced myelosuppression. This will allow us to develop novel and mechanism-based interventions to circumvent IR-induced BM toxicity, which are urgently needed as new medical countermeasures against nuclear terrorism. In addition, these new interventions could markedly improve the therapeutic efficacy of conventional cancer therapy by reducing normal tissue injury induced by radiation and chemotherapy.